Abstract

Mechanism Based Repurposing of Neurodegenerative Disease Drugs for Breast Cancer Treatment

Ajay Rana, Endowed Professor & Director of Research, University of Illinois at Chicago

Breast cancer account for the second most cause of cancer related mortality in women. The detailed underlying molecular mechanisms of breast cancer pathogenesis of all the sub-types are not fully understood, however the roles of Estrogen Receptor (ER), Progesterone Receptor (PR), and Epidermal Growth Factor Receptor 2 (HER2) in promoting growth, survival, invasion and acquired resistance to therapies have begun to unravel. The prognosis of ER+ breast cancer that accounts for 60-70% of breast cancers is favorable, however it is dismal for the remaining Triple Negative (TNBC) and HER2+ breast cancer. Quite unexpectedly, we landed onto identifying a pathway that seems to be important for TNBC breast cancer cell survival. While dissecting the MLK3-mediated signaling pathway, we observed a robust interaction between MLK3 and p21-activated kinase 1 (Pak1). Subsequent detail studies showed that Pak1 was phosphorylated and activated by MLK3 in breast cancer cells. Furthermore, the MLK3, Pak1 and NF-?B activities were significantly higher in ER- primary human breast tumor. These results are intriguing because there is little doubt that level and activity of Pak1 are frequently increased in various cancers, including breast cancer. Our results clearly showed that the small molecule inhibitor of MLKs that went for clinical trial for Parkinson’s Disease can specifically induce cell death in TNBC, suggesting that this pathway could serve as a viable target for TNBC breast cancer.